Osteoporosis is a common disease that causes significant morbidity and mortality. The widespread prevalence of osteoporosis results in >2 million fractures yearly with an estimated cost of $17 billion in the US alone. Current agents are unable to completely restore skeletal integrity in patients with established osteoporosis and are inadequate to match the anticipated rise in fracture incidence in our aging population. Thus, continued efforts to develop innovative, evidence-based osteoporosis treatment strategies are crucial. The scientific focus of this proposal is the optimization of combination antiresorptive an anabolic osteoporosis therapies. In contrast to disappointing results from combining bisphosphonates with teriparatide (hPTH1-34 or TPTD), the combination of denosumab (DMAB), a monoclonal antibody that binds to receptor activator of nuclear factor-kB ligand (RANKL), and TPTD was recently reported to increase bone mineral density more than either drug alone. One specific aim of this proposal is to further understand the mechanisms underlying the additive properties of this therapeutic combination by assessing the changes in bone structure, microarchitecture, and strength in this same cohort. Specifically, high-resolution peripheral quantitative computed tomography of the distal tibia and radius will be used to compare the effects of combination TPTD and DMAB therapy versus each individual agent on cortical and trabecular volumetric bone density, cortical thickness and porosity, trabecular microarchitecture, and estimated bone strength (via micro finite element analysis). A further aim of this proposal is to expand on the recent novel finding from the above study that bone resorption is potently and equally suppressed when DMAB and TPTD are combined than when DMAB is given alone. Specifically, this proposed study will test the hypothesis that DMAB, but not alendronate, will fully inhibit the acute pro-resorptive effect of an increased dose of TPTD in postmenopausal osteoporotic women. If confirmed, this will suggest that higher doses of TPTD (40-mcg), when combined with DMAB, may improve skeletal integrity significantly more than DMAB and standard dose TPTD (20-mcg). Forty postmenopausal osteoporotic women aged 60+ will be enrolled in a short-term, open label randomized controlled trial. Subjects will be randomized to receive DMAB or alendronate therapy for 8 weeks. Subjects will also receive a single injection of TPTD 40-mcg both before and after the 8 weeks of antiresorptive therapy. The relative ability of each antiresorptive agent to inhibit TPTD-induced bone resorption will be evaluated by measuring biochemical markers of bone resorption prior to and 4 hours after the TPTD injection both at baseline and after 8-weeks of antiresorptive therapy. This study will provide a better mechanistic understanding of effects of combined osteoclast inhibition and osteoblast stimulation and aid in the design of innovative clinical trials designed to improve skeletal integrity in women and men at high risk for fracture.